Genetic and adoptive transfer experiments demonstrate an unexpected protective role of B cells in mucosal immunologic homeostasis and resistance to inflammatory bowel disease. However, the identity and functional mechanisms of this regulatory B cell population are poorly understood, and their role in biologically divergent models of colitis are not delineated. Our preliminary studies reveal that a phenotypically distinct B cell population mediates protection in the CD4CD45RBhi and Gai2-/- T cell transfer colitis models. Notably, this protection requires CD8a+ T cells, and is associated with significant expansion of central CD8a T and NK T cells, and intestinal CD4+CD8a+ DP T cells. Based on these findings and recent literature, we propose that regulatory mesenteric B cells, due to their access to the enteric antigenic environment, BCR antigen specificity, and cell-interaction molecules, are exquisitely proficient for activation of an NKT cell population cognate for enteric antigens. Upon activation, these NKT cells drive the anti-inflammatory differentiation of central and intestinal DCs, who are rendered incompetent to induce and active colitigenic CD4 T cells, and instead promote the differentiation of non-inflammatory CD4CD8aa T cells. To test and refine this model, the present proposal will define the phenotype and anatomic location of the protective B cell populations, and use genetic methods to identify cell-interaction and effector molecules through which they carry out their protective effect. The expanded T cell subsets, and central and intestinal dendritic cells, will be characterized with regard to activation state and anatomic abundance, and by genetic means assess B cell traits required for their expansion. Direct cell transfer experiments will establish whether these cells are required for the protective effect of B cells in these and two biologically divergent colitis systems.